Primary amino acid sequences of ERK-2 from human, M. musculus, R. norvegicus, and X. laevis were examined to determine the number of potential residues reactive toward 4-HNE, namely cysteine, histidine, and lysine, and to establish that these sites are conserved across experimental species when compared with the human sequence. Despite subtle differences in their primary sequences, all species variants of ERK-2 possessed the 7 cysteine, 13 histidine, and 23 lysine residues that were observed within the human, primary ERK-2 sequence, indicating that the mechanistic modification of nucleophilic sites by 4-HNE would act through conserved residues.